Derivatives of the pyrazolo[1,5-a]pyrimidine acetamide DPA-713 as translocator protein (TSPO) ligands and pro-apoptotic agents in human glioblastoma

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• 作者：Eryn L Werry^a ; ¹ ; Victoria A. King^b ; ¹ ; Melissa L Barron^a ; Samuel D. Banister^c ; Renee Sokias^c ; Michael Kassiou^c ; ^{michael.kassiou@sydney.edu.au}
• 关键词：BrdU ; 5-bromo-2&prime ; -deoxyuridine ; DMEM/F12 ; Dulbecco's modified eagle's medium ; Ham's nutrient mixture F-12 ; DMSO ; dimethyl sulfoxide ; EDTA ; ethylenediaminetetraacetic acid ; LLE ; lipophilic ligand efficiency ; MEM ; minimum essential medium ; PET ; positron emission tomography ; SPECT ; single-photon emission computed tomography ; TSPO ; translocator protein
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：186-192
• 全文大小：768 K
• 卷排序：96

文摘

The 18 kDa translocator protein (TSPO) is a target for novel glioblastoma therapies due to its upregulation in this cancer and relatively low levels of expression in the healthy cortex. The pyrazolo[1,5-a]pyrimidine acetamides, exemplified by DPA-713 and DPA-714, are a class of high affinity TSPO ligands with selectivity over the central benzodiazepine receptor. In this study we have explored the potential anti-glioblastoma activity of a library of DPA-713 and DPA-714 analogues, and investigated the effect of amending the alkyl ether chain on TSPO affinity and functional potential. All ligands demonstrated nanomolar affinity for TSPO, but showed diverse functional activity, for example DPA-713 and DPA-714 did not affect the proliferation or viability of human T98G glioblastoma cells, while the hexyl ether and benzyl ether derivatives decreased proliferation of T98G cells without affecting proliferation in human fetal glial SVGp12 cells. These ligands also induced apoptosis and dissipated T98G mitochondrial membrane potential. This suggests that the nature of the alkyl ether chain of pyrazolo[1,5-a]pyrimidine acetamides has little influence on TSPO affinity but is important for functional activity of this class of TSPO ligands.